BCMA bispecifics: breaking the chains of resistance

In this issue of Blood, Lee et al¹ systematically describe the mechanisms of primary resistance to BCMA×CD3 bispecific antibodies in multiple myeloma and provide insights that may help to overcome the initial refractoriness seen in up to 40% of patients.

Off-the-shelf bispecific antibodies targeting BCMA show strong single-agent activity in multiple myeloma. However, not all patients respond, and resistance can develop even after an initial response. A number of studies have investigated the mechanisms of secondary resistance to bispecifics, and it is now accepted that (functional) antigen loss due to biallelic TNFRSF17 deletions or mutations,² but also T-cell exhaustion³ and an immunosuppressive microenvironment,^4,5 can ultimately lead to disease relapse. Strategies to counteract immune suppression and restore T-cell function have entered clinical practice. Fixed-duration treatments as well as combination therapies are actively being pursued with the goal to either deplete regulatory T cells, regulatory B cells, and myeloid-derived suppressor cells (eg, with daratumumab, NCT04722146) or to reverse T-cell anergy by cotreatment with immunomodulators (NCT05243797, NCT06465316, NCT06215118) or immune checkpoint inhibition (NCT05338775). Meanwhile, primary resistance, which affects up to 40% of patients across all trials and agents, has mostly been linked to baseline T-cell exhaustion,⁶ and other non–T-cell factors contributing to primary resistance remain largely unexplored.

In this issue of Blood, Lee et al set out to solve this mystery by providing a holistic view of the determinants that drive primary resistance to BCMA×CD3 bispecifics in multiple myeloma (see figure). Using a TNFRSF17-transduced cell line model, the authors elegantly dissect that a stepwise increase in soluble BCMA (sBCMA) levels impairs the specific binding capacity of bispecifics, ultimately leading to their complete abrogation. Interestingly, this “sink effect” appears to primarily affect the Food and Drug Administration–approved bispecifics teclistamab and elranatamab, whereas alnuctamab, a next-generation bispecific with an improved (2:1) BCMA binding configuration, is less affected by high sBCMA concentrations. Given this finding, it is unfortunate that further development of alnuctamab has been halted.

High sBCMA levels have long been suspected as a key determinant contributing to primary resistance to bispecifics, mainly because elevated sBCMA can reduce the target availability of bispecifics. Using mature outcome data from the MajesTEC-1 trial (n = 163 patients, NCT04557098), the authors are the first to demonstrate a significant relationship between baseline sBCMA levels, response rates, and outcome. A previous study by Girgis et al, using the same but less mature dataset (n = 147), was unable to confirm this association, despite reporting a median baseline sBCMA of 54.9 ng/mL and 304 ng/mL in teclistamab responders vs nonresponders, respectively.⁷ The thresholds used to define high sBCMA differed in the 2 analyses, and the clinically meaningful threshold of 400 ng/mL proposed by Lee et al certainly requires further validation in separate studies.

What other determinants can increase efficacy in the presence of high sBCMA? First, the effector-to-target (E:T) ratio is important. Lee et al show that higher ratios result in improved efficacy of bispecifics irrespective of sBCMA levels. These data are supported by a very recent study by Verkleij et al, which describes that the in vitro killing capacity of teclistamab and talquetamab increases proportionally with the E:T ratio.⁵ Although T cells are generally considered to be efficient serial killers, the in vitro experiments performed by Lee et al suggest that T cells eliminate only 5 to 10 tumor cells at a time. However, T-cell expansion and proliferation are difficult to replicate in vitro, making the actual number of kills per T cell difficult to determine. The density of surface receptors is another critical factor that may influence this “numbers game,” and it is noteworthy that although a limited number of surface-expressed antigens may be sufficient for T cell–mediated elimination, T-cell proliferation appears to depend more on the abundance of these antigens. Building on previous data,⁸ Lee et al show that γ-secretase inhibition enhances tumor cell killing by normalizing elevated sBCMA levels, whereas the previously reported increase in membrane-bound BCMA does not consistently improve cytolytic activity, but rather depends on tumor burden and E:T ratios. Clinical trials testing BCMA×CD3 bispecifics in combination with the γ-secretase inhibitor nirogacestat are ongoing (NCT05259839, NCT04722146). Early results from the phase 1b MajesTEC-2 trial show encouraging overall response rates of up to 92.3% for teclistamab-nirogacestat; however, safety is a concern with 6 of 28 (21.4%) treatment-related deaths reported in the first interim analysis.⁹ 

In conclusion, the findings by Lee et al are the first to mechanistically unravel primary resistance to BCMA×CD3 bispecifics in multiple myeloma. Despite these findings, several questions remain. High tumor burden and extramedullary disease (EMD) result in poor responses to otherwise highly effective therapies such as GPRC5D×CD3 bispecifics or BCMA-directed chimeric antigen receptor T cells, and soluble BCMA may not fully explain the inferior outcome seen with these agents. In addition, the effector T-cell compartment is diverse, and our understanding of how specific T-cell clonotypes expand and mediate killing in response to bispecific antibodies is still in its infancy. In this sense, EMD has recently been characterized as having an immunosuppressive microenvironment reminiscent of solid tumors, where T-cell redirection therapies are also more challenging.¹⁰ 

To move forward, debulking strategies, especially for patients with high tumor burden, will certainly be helpful to reduce sBCMA levels and achieve a more favorable E:T ratio. Adequate dosing and measures to ensure antigen abundance, especially in the initial phase of therapy when sBCMA levels and tumor cells are high, will equally be necessary to overcome the primary refractoriness to BCMA×CD3 bispecifics.

Conflict-of-interest disclosure: J.M.W. declares consultancy for Johnson & Johnson, Sanofi, Takeda, Pfizer, Oncopeptides, Skyline Dx; honoraria from GlaxoSmithKline (GSK), Johnson & Johnson, Pfizer, and Beigene; and research support from Bristol Myers Squibb (BMS). L.R. declares consultancy for Johnson & Johnson, Amgen, GSK, Pfizer, BMS, and Sanofi; honoraria from Johnson & Johnson, GSK, Pfizer, BMS, and Sanofi; and research funding from Skyline Dx and BMS.